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Design, fabrication, and characterization of a novel surface acoustic wave (SAW) biosensor in complementary metal-oxide semiconductor (CMOS) technology are introduced. The biosensor employs a streptavidin/biotin-based five-layer immunoassay for detecting a prominent breast cancer biomarker, mammoglobin (hMAM). There is a growing demand to develop a sensitive and specific assay to detect biomarkers in serum that could be used in the early detection of breast cancer, determining prognosis and monitoring therapy. CMOS-SAW devices present a viable alternative to the existing biosensor technologies by providing higher sensitivity levels and better performance at low costs. Two architectures (circular and rectangular) were developed and respective tests were presented for performance comparison. The sensitivities of the devices were analyzed primarily based on center frequency shifts. A frequency sensitivity of 8.704 pg/Hz and a mass sensitivity of 2810.25 m2 /kg were obtained. Selectivity tests were carried out against bovine serum albumin. Experimental results indicate that it is possible to attach cancer biomarkers to functionalized CMOS-SAW sensor surfaces and selectively detect hMAM antigens with improved sensitivities, lowered costs, and increased repeatability of fabrication.